The Animal Models Core (D) is located within the Mycobacteriology Laboratory on the campus of Colorado State University. The Animal Infection Core is multidisciplinary with the expertise, personnel and facilities to model Mtb infection in guinea pigs with drug susceptible and resistant human clinical isolates as well as laboratory Mtb strains with targeted gene mutations. Our laboratory is also experienced and well equipped to model Mtb infection in guinea pigs with concurrent non-communicable diseases that are known TB risk factors in humans. Relevant to this proposal, we have developed the first ever model of Mtb infection in guinea pigs with diet-induced insulin resistance and type 2 diabetes that accurately mimics the comorbidity of tuberculosis and emerging noncommunicable diseases. In addition, we have designed and validated novel strategies to quantify pulmonary and extra-pulmonary tuberculosis disease burden in guinea pigs in response to experimental aerosol infection with drug susceptible and multi-drug resistant strains of Mycobacterium tuberculosis. We have recently characterized the profound alterations in systemic and cellular metabolism in response to Mycobacterium tuberculosis infection alone and demonstrated how preexisting alterations in host metabolism influences host susceptibility and in vivo disease progression. The Animal Models Core will parallel human cohort studies to 1) identify host metabolic determinants of tuberculosis disease control and progression and 2) use metabolomics to discover bacterial determinates of drug resistance and the discovery of host- and pathogen-derived biomarkers for tuberculosis diagnosis. Using the guinea pig model to study altered host metabolism associated with Mycobacterium tuberculosis infection has not only improved our understanding of the host-pathogen interaction but has identified potentially important therapeutic strategies that can be used as adjunct therapy in combination with conventional antimicrobial drug therapy. To fully exploit this model, the substantial existing core capabilities will be expanded to discover and validate additional biomarkers of altered host metabolism in guinea pigs infected with drug susceptible and drug resistant Mycobacterium tuberculosis.